The serine proteases are a class of enzymes which includes elastase, chymotrypsin, cathepsin G, trypsin and thrombin. These proteases have in common a catalytic triad consisting of Serine-195, Histidine-57 and Aspartic acid-102 (chymotrypsin numbering system). Human neutrophil elastase (HNE) is a proteolytic enzyme secreted by polymorphonuclear leukocytes (PMNs) in response to a variety of inflammatory stimuli. This release of HNE and its extracellular proteolytic activity are highly regulated and are normal, beneficial functions of PMNs. The degradative capacity of HNE, under normal circumstances, is modulated by relatively high plasma concentrations of(xcex11-proteinase inhibitor (xcex11-PI). However, stimulated PMNs produce a burst of active oxygen metabolites, some of which (hypochlorous acid for example) are capable of oxidizing a critical methionine residue in xcex11-PI. Oxidized xcex11-PI has been shown to have limited potency as an HNE inhibitor and it has been proposed that alteration of this protease/antiprotease balance permits HNE to perform its degradative functions in localized and controlled environments.
Despite this balance of protease/antiprotease activity, there are several human disease states in which a breakdown of this control mechanism is implicated in the pathogenesis of the condition. Improper modulation of HNE activity has been suggested as a contributing factor in adult respiratory distress syndrome, septic shock and multiple organ failure. A series of studies also have indicated the involvement of PMNs and neutrophil elastase in myocardial ischemia-reperfusion injury. Humans with below-normal levels of xcex11-PI have an increased probability of developing emphysema. HNE-mediated processes are implicated in other conditions such as arthritis, periodontal disease, glomerulonephritis, dermatitis, psoriasis, cystic fibrosis, chronic bronchitis, atherosclerosis, Alzheimer""s disease, organ transplantation, corneal ulcers, and invasion behavior of malignant tumors.
There is a need for effective inhibitors of HNE as therapeutic and as prophylactic agents for the treatment and/or prevention of elastase-mediated problems.
The present invention provides compounds which are useful as serine protease inhibitors, including human neutrophil elastase. These compounds are characterized by their relatively low molecular weight, high potency and selectivity with respect to HNE. Additionally, certain compounds of the invention have demonstrated oral bioavailability as exhibited by their higher blood levels after oral dosing. Oral bioavailability allows oral dosing for use in chronic disease, with the advantages of self-administration and decreased cost over other means of administration. The compounds described herein can be used effectively to prevent, alleviate or otherwise treat disease states characterized by the degradation of connective tissue by proteases in humans.
The present invention provides compounds comprising oxadiazole, thiadiazole or triazole ring structures, and can be generically described by the formula: 
wherein Z is a serine protease binding moiety, preferably an elastase binding moiety, and most preferably a human neutrophil elastase binding moiety. Specifically, Z is a carbonyl containing group, preferably xcex1-amino carbonyl containing group where the carbonyl carbon is covalently attached to the carbon of the heterocycle.
R1 is alkyl, alkenyl or alkynyl optionally substituted with 1 or more, preferably 1-3, halo, hydroxyl, cyano, nitro, haloalkyl, alkylamino, dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide or xe2x80x94Oxe2x80x94(C5-C6)aryl; hydroxyl, amino, alkylamino or dialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkenylcycloalkenyl, (C5-C12)aryl, (C5-C12)arylalkyl, (C5-C12)arylalkenyl, fused (C5-C12)aryl-cycloalkyl or alkyl fused (C5-C12)aryl-cycolalkyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, xe2x80x94Oxe2x80x94(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio.
X and Y are independently O, S or N, wherein N is optionally substituted with alkyl or alkenyl optionally substituted with 1-3 halo atoms; (C5-C6)aryl, arylalkyl or arylalkenyl optionally comprising 1-3 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio. Preferably, at least one of X or Y is N. It will be understood that where X or Y is a substituted N, both X and Y are N. Preferably, the compounds of the present invention comprise 1,2,4-oxadiazole (i.e., X is O; Y is N) or 1,3,4 oxadiazole rings (i.e., X is N; Y is O).
The compounds of the present invention may be conveniently categorized as Groups I through VI.
In one preferred embodiment, the invention provides compounds of the formula (Group I): 
wherein X, Y and R, are described above;
R2 and R3 are independently or together H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl; thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; xe2x80x94RCORxe2x80x2, xe2x80x94RCOORxe2x80x2, xe2x80x94RNRxe2x80x2Rxe2x80x3R or xe2x80x94RC(O)NRxe2x80x2Rxe2x80x3 where R is alkyl or alkenyl, and Rxe2x80x2,Rxe2x80x3 and Ro are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C5-C12)aryl, (C5-C12)arylalkyl or (C5-C12)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, xe2x80x94Oxe2x80x94(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
A is a direct bond, xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94NHxe2x80x94S(O)2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94Cxe2x80x94 or an amino acid selected from, but not limited to, proline, isoleucine, cyclohexylalanine, cysteine optionally substituted at the sulfur with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; phenylalanine, homo-phenylalanine, dehydrophenylalanine, indoline-2-carboxylic acid; tetrahydrosioquinoline-2-carboxylic acid optionally substituted with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylanino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; tryptophan, tyrosine, serine or threonine optionally substituted with alkyl or aryl; histidine, methionine, valine, norvaline, norleucine, octahydroindole-2-carboxylic acid; asparagine, glutamine, omithine and lysine optionally substituted at the side chain nitrogen with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N, O and S; and
R4 is H, alkyl, alkenyl or alkynyl; or cycloalkyl, alkylcycloalkyl, (C5-C12)aryl, (C5-C12)arylalkyl, fused (C5-C12)aryl-cycloalkyl or fused alkyl (C5-C12)aryl-cycloalkyl optionally comprising one or more heteroatoms selected from N, O and S, and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamido, alkylthio or haloalkylthio or is absent.
In a preferred embodiment, X is N and Y is O In another preferred embodiment, X is O and Y is N. Preferably, R4xe2x80x94A is an arylalkyloxycarbonyl such as benzyloxycarbonyl; alkoxycarbonyl, arylsulfonyl, alkylsulfonyl or alkyl.
Preferably, R2 and R3 are alkyl such as methyl or isopropyl, or H. In one preferred embodiment, R2 is isopropyl and R3 is H.
In a preferred embodiment of the invention, R1 is an optionally substituted aryl or arylalkyl group, such as an xcex1,xcex1-dimethylbenzyl, benzyl or phenyl group. According to several preferred embodiments, the benzene ring is substituted with an alkyl, such as methyl; with a haloalkyl, such as trifluoromethyl; or with a dialkylamino, preferably dimethylamino. In yet another embodiment, R1 is a fused arylalkyl group such as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl such as 3,4-methylenedioxybenzyl. In another embodiment, R1 is an alkyl group, preferably (C1-C8)alkyl, either straight chain or branched, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc.
The present invention further provides compounds of the formula (Group II): 
wherein
X, Y, R1, R2 and R3 are as described above;
B is xe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94OC(O)xe2x80x94 or xe2x80x94CH2C(O)xe2x80x94;
R6 is 
xe2x80x83wherein
Rxe2x80x22 and Rxe2x80x23 are independently or together H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; xe2x80x94RCORxe2x80x2, xe2x80x94RCOORxe2x80x2, xe2x80x94RNRxe2x80x2Rxe2x80x3Rxc2x0 or xe2x80x94RC(O)NRxe2x80x2Rxe2x80x3 where R is alkyl or alkenyl, and Rxe2x80x2, Rxe2x80x3 and Ro are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C5-C12)aryl, (C5-C12)arylalkyl or (C5-C12)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, xe2x80x94Oxe2x80x94(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
R13 is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S, and optionally substituted with halo or alkyl;
R14 is H, alkyl, alkenyl, amino, alkylamino, dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl, alkyl fused aryl-cycloalkyl or aryloxycarboxamide optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, arylalkylcarboxamide, alkylthio or haloalkylthio;
R15 is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S; and
W is O or S; or C or N optionally substituted with H, alkyl or aryl.
In a preferred embodiment, X is N and Y is O. In another preferred embodiment, X is O and Y is N. According to several preferred embodiments, R13 is an optionally substituted phenyl or benzyl; pyridyl, piperidinyl, alkyl or H or a fused ring system such as 3,4-methylenedioxybenzyl; R14 is optionally substituted amino or an arylalkyloxycarboxamide such as benzyloxycarboxamide; and R15 is H or halo.
Preferably, R2 is isopropyl and R3 is H.
In a preferred embodiment of the invention, R1 is an optionally substituted aryl or arylalkyl group, such as a xcex1,xcex1-dimethylbenzyl, benzyl or phenyl group. According to several preferred embodiments, the benzene ring is substituted with an alkyl, such as methyl; with a haloalkyl, such as trifluoromethyl; or with a dialkylamino, preferably dimethylamino. In yet another embodiment, R1 is a fused arylalkyl group such as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl such as 3,4-methylenedioxybenzyl. In another embodiment, R1 is an alkyl group, preferably (C1-C8)alkyl, either straight chain or branched, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc.
The present invention also provides compounds of the formula (Group III): 
wherein X, Y, R1, R2, R3 and B are as described above; and R6 is of formula (I): 
where m is 0 or 1; n is 0 or 1;
D is a direct bond or an amino acid selected from, but not limited to, proline, isoleucine, cyclohexylalanine, cysteine optionally substituted at the sulfur with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; phenylalanine, homo-phenylalanine, dehydrophenylalanine, indoline-2-carboxylic acid; tetrahydrosioquinoline-2-carboxylic acid optionally substituted with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; tryptophan, tyrosine, serine or threonine optionally substituted with alkyl or aryl; histidine methionine, valine, norvaline, norleucine, octahydroindole-2-carboxylic acid; asparagine, glutamine, ornithine and lysine optionally substituted at the side chain nitrogen with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteratoms selected from N, O and S;
A is a direct bond, xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94OC(O)xe2x80x94 or xe2x80x94Cxe2x80x94; and
R14 is H, alkyl, alkenyl, amino, alkylamino or dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl; fused arylycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteratoms selected from N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio.
Alternatively, R6 is of formula (II): 
where
W is S or O;
R8 is alkylamino, dialkylamino or amino;
R9 is H, alkyl or halo.
In a preferred embodiment, X is N and Y is O. In another preferred embodiment, X is O and Y is N. According to one embodiment, where R6 is of formula (I), m is 1, n is 0. In another embodiment, m and n are 1. Preferably, R14 is benzyl, A is OC(O)xe2x80x94 and D is Val.
Preferably, R2 is isopropyl and R3 is H.
In a preferred embodiment of the invention, R1 is an optionally substituted aryl or arylalkyl group, such as a xcex1,xcex1-dimethylbenzyl, benzyl or phenyl group. According to several preferred embodiments, the benzene ring is substituted with an alkyl, such as methyl; with a haloalkyl, such as trifluoromethyl; or with a dialkylamino, preferably dimethylamino. In yet another embodiment, R1 is a fused arylalkyl group such as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl such as 3,4-methylenedioxybenzyl. In another embodiment, R1 is an alkyl group, preferably (C1-C8) alkyl, either straight chain or branched, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc.
According to one embodiment, W is S; R8 is amino and R9 is H.
In yet a further embodiment of the invention of Group (III) compounds, R6 is aryl, arylalkyl, cycloalkyl or alkylcycloalkyl. According to one embodiment, R6xe2x80x94B is Cbz.
The present invention further provides compounds of the formula (Group IV): 
wherein
X, Y, R1, R2 and R3 are as described above;
R10 is (C5-C6)aryl, (C5-C6)arylalkyl, (C5-C6)arylalkenyl, cycloalkyl, fused aryl-cycloalkyl optionally comprising one or more heteroatoms selected from N, S and non-peroxide O, and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkylthio or haloalkylthio;
D is a direct bond, xe2x80x94C(O)xe2x80x94, or an amino acid selected from, but not limited to, proline, isoleucine, cyclohexylalanine, cysteine optionally substituted at the sulfur with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; phenylalanine, homo-phenylalanine, dehydrophenylalanine, indoline-2-carboxylic acid; tetrahydrosioquinoline-2-carboxylic acid optionally substituted with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; tryptophan, tyrosine, serine or threonine optionally substituted with alkyl or aryl; histidine methionine, valine, norvaline, norleucine, octahydroindole-2-carboxylic acid; asparagine, glutamine, ornithine and lysine optionally substituted at the side chain nitrogen with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteratoms selected from N, O and S;
A is a direct bond, xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94NHxe2x80x94S(Q)2xe2x80x94, xe2x80x94S(O)2xe2x80x94NHxe2x80x94, xe2x80x94OC(O)NHxe2x80x94, xe2x80x94OC(O)xe2x80x94 or xe2x80x94Cxe2x80x94; and R14, is as described above.
In a preferred embodiment, X is N and Y is O. In another preferred embodiment, X is O and Y is N. Preferably, D is Val, A is xe2x80x94OC(O)xe2x80x94 and R14 is aryl or arylalkyl such as benzyl. In a preferred embodiment, R10 is (C5-C6)aryl or (C5-C6)arylalkyl, preferably benzyl, or a fused aryl-cycloalkyl such as an indanyl group. According to another preferred embodiment, D is xe2x80x94C(O)xe2x80x94, and R14xe2x80x94A is pyrrole.
Preferably, R2 is isopropyl and R3 is H.
In a preferred embodiment of the invention, R1 is an optionally substituted aryl or arylalkyl group, such as xcex1,xcex1-dimethylbenzyl, benzyl or phenyl group. According to several preferred embodiments, the benzene ring is substituted with an alkyl, such as methyl; with a haloalkyl, such as trifluoromethyl; or with a dialkylamino, preferably dimethylamino. In yet another embodiment, R1 is a fused arylalkyl group such as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl such as 3,4-methylenedioxybenzyl. In another embodiment, R1 is an alkyl group, preferably (C1-C8)alkyl, either straight chain or branched, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc.
The present invention additionally provides compounds of the formula (Group V): 
wherein X, Y, R1, R2, R3, Rxe2x80x22 and Rxe2x80x23 are as described above; and
R11, R12 and E together form a monocyclic or bicyclic ring comprising 5-10 atoms selected from C, N, S and O; said ring containing 1 or more keto groups; and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamido, alkylthio, haloalkylthio; cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C5-C12)aryl, (C5-C12)arylalkyl, ((C5-C12)arylalkyl)OC(O)NHxe2x80x94 or (C5-C12)arylalkenyl optionally comprising one or more heteroatoms selected from N, S and non-peroxide O, and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, xe2x80x94C(O)O(alkyl), xe2x80x94C(O)(alkyl), alkylcarboxamido, alkylthio or haloalkylthio.
In a preferred embodiment, X is N and Y is O. In another preferred embodiment, X is O and Y is N.
Preferably, R2 is isopropyl and R3 is H.
In a preferred embodiment of the invention, R1 is an optionally substituted aryl or arylalkyl group, such as a xcex1,xcex1-dimethylbenzyl, benzyl or phenyl group. According to several preferred embodiments, the benzene ring is substituted with an alkyl, such as methyl; with a haloalkyl, such as trifluoromethyl; or with a dialkylamino, preferably dimethylamino. In yet another embodiment, R1 is a fused arylalkyl group such as methylenenaphthyl; or a fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl such as 3,4-methylenedioxybenzyl. In another embodiment, R1 is an alkyl group, preferably (C1-C8)alkyl, either straight chain or branched, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc.
According to one embodiment of the invention, R11, R12, and E together form a ring structure of formulas (I) or (Ia): 
wherein A is as described above for Group (IV);
V1 V2, V3 and V4 are independently or together C or N;
where V3 is C; R13 is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S, and optionally substituted with halo or alkyl, R14 is H, alkyl, alkenyl, amino, alkylamino or dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl, arylalkylxoxycarbonyl or arylalkylcarboxamide optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio; and
W1, W2 and W3 are independently selected from N optionally substituted with alkyl; C, S and O.
According to one preferred embodiment, V4 is N; and V1, V2 and V3 are C. Preferably, R13 is H or halo; R14xe2x80x94A is CbNH, amino or H; and Rxe2x80x22 and Rxe2x80x23 are H. Preferably, R11, R12 and E together form a ring of formula (I). In a particular embodiment, R13 is H or F; and R14xe2x80x94Axe2x80x94 is H or H2Nxe2x80x94. Where R11, R12 and E together form a ring of formula (Ia), W1 is preferably S, and W2 and W3 are C.
In another embodiment, R11, R12 and E together form a ring of formula (II) 
wherein A, R13 and R14 are as described above;
Preferably, Rxe2x80x22 and Rxe2x80x23 are H. According to one embodiment, R13 is 1-piperidinyl; and R14xe2x80x94A is CbzNH. Alternatively, R13 is H; and R14xe2x80x94A is amino, alkylamino or dialkylamino. In another preferred embodiment, R13 is halo; and R14xe2x80x94A is CH3xe2x80x94Oxe2x80x94C(O)xe2x80x94. In yet another embodiment, R13 is H; and R14xe2x80x94A is CbzNH.
According to another embodiment of the invention, R11, R12 and E form a ring of formula (III) or (IV): 
wherein
A is a direct bond, xe2x80x94Cxe2x80x94 or xe2x80x94C(O)xe2x80x94;
R13, R14 and R15 are as defined above.
According to a particular embodiment, R11, R12 and E form a ring of formula (III); and xe2x80x94Axe2x80x94R13 is xe2x80x94C(O)phenyl; R15 is H; and Rxe2x80x22 and Rxe2x80x23 are H.
In another embodiment, R11, R12 and E form a ring of formula (IV); and xe2x80x94Axe2x80x94R13 is xe2x80x94C(O)phenyl; R15 is H; and Rxe2x80x22 and Rxe2x80x23 and H.
In another embodiment of the invention, R1, R2 and E form a ring of formula (V): 
wherein (v)
W is S, SO, SO2 or C;
n is 0, 1 or 2;
R13 and R14 are defined above; and
G is xe2x80x94NHC(O)xe2x80x94, OC(O)NHxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NHS(O)2xe2x80x94 or a direct bond.
According to one embodiment, n is 0 and W is S, where preferably R14xe2x80x94G is H. Preferably, R13 is optionally substituted benzyl or phenyl.
In another embodiment, n is 1 and W is C. Preferably, R14xe2x80x94G is an arylalkyloxycarboxamide, for example, CbzNHxe2x80x94. In a preferred embodiment, R13 is H or phenyl substituted with halo. Preferably, Rxe2x80x22 and Rxe2x80x23 are H.
The invention further provides compounds wherein R11, R12 and E form a ring of formulas (VI), (VIa), (VII) or (VII): 
wherein
R13 is as defined above, or is xe2x95x90CHxe2x80x94R15 or R15 where R15 is pyridinyl, phenyl or benzyl optionally substituted with halo, dialkylamino or C(O)OCH3;
R14 and Rxe2x80x214 are independently or together H, alkyl, alkenyl, CH3C(O)xe2x80x94; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl, aryloxycarbonyl or arylalkyloxycarbonyl optionally comprising 1 or more heteratoms selected from N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio; and
R16, R17, Rxe2x80x216 and Rxe2x80x217 are independently or together H, alkyl, alkenyl, alkylthio, alkylthioalkyl; or cycloalkyl, cycloalkenyl, alkylcycloalkyl, aryl, arylalkyl or arylalkenyl optionally substituted with guanidine, carboalkoxy, hydroxyl, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine.
Preferred compounds are of formula (VI) or (VIa) where R13 is xe2x95x90CHxe2x80x94R15 or R15; and R14 is H, alkyl, CH3C(O)xe2x80x94, Cbz or benzyl optionally substituted with alkyl, halo or alkylamino; or 3,4-methylenedioxybenzyl or 3,4-ethylenedioxybenzyl; and Rxe2x80x22 and Rxe2x80x23 are H. Preferably, R13 is xe2x95x90CHR15 where R15 is phenyl or benzyl optionally substituted with halo or xe2x80x94C(O)CH3.
In a further embodiment, R11, R12 and E form a ring of formula (IX) or (IXa): 
wherein
U, V, W and Y are independently or together N, C, C(O), N(R13) where R13 is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S, and optionally substituted with halo or alkyl; N(R14) where R14 is H, alkyl, alkenyl, or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteratoms selected from N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio; or C(R16)(R17) where R16 and R17 are independently or together H, alkyl, alkylthio, alkylthioalkyl; a carboxylic acid ester of the formula xe2x80x94(CH2)mC(O)OR or an N-substituted alkylamide of the formula xe2x80x94(CH2)mC(O)NRRxe2x80x2 where m is 1 to 6 and R and Rxe2x80x2 are independently or together H or alkyl; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising one or more heteroatoms selected from N, S and non-peroxide O and optionally substituted with amino, alkylamino, dialkylamino, guanidine, carboalkoxy, keto, hydroxyl, alkyl, haloalkyl, alkylthio alkylguanidine, dialkylguanidine or amidine; or together form a cyclic ring structure comprising 4-8 atoms selected from C, N, O and S.
In one preferred embodiment, U is C(R16)(R17), V is N, W is N(R14) and Y is C(O), where preferably Rxe2x80x22 and Rxe2x80x23 are H; R16 is phenyl or benzyl; R17 is H; and R14 is H or benzyl optionally substituted with alkyl, halo, or alkylamine.
In another preferred embodiment, U is C(O); V is N, W is N, N(R13) or N(R14); and Y is C(R16)(R17), where preferably Rxe2x80x22 and Rxe2x80x23 are H; R14 is H; R16 is H, alkyl, optionally substituted aryl or arylalkyl, preferably benzyl or phenyl optionally substituted with dialkylamino or hydroxyl; pyridinyl, methylene pyridinyl; fused aryl such as an indolyl, indolemethylene; or a carboxylic acid ester or N-substituted alkyl amide, as defined above; and R17 is H, alkyl, succinimidyl, aryl or arylalkyl.
In yet another preferred embodiment, U is C(O), V is N, W is N, N(R13) or N(R14); and Y is N(R13), where preferably Rxe2x80x22 and Rxe2x80x23 are H; W is NH; R13 is arylalkyl; and R14 is H.
In a further embodiment, U is C(R16)(R17); V is N; W is N or N(R13); and Y is C(O). Preferably, R13 and R16 are aryl; and R17 is H.
Where R11, R12 and E form a ring of formula (IXa); W is typically N(R13) where R13 is aryl or cycloalkyl such as piperidinyl.
In another embodiment, R16 and R17 form a cyclic ring structure, such as a cyclopentyl or cyclohexyl group.
The invention further provides compounds of the formula (Group VI): 
wherein X, Y, R1, R2 and R3 are as described above, and R11, R12 and E together form a ring of formula (X): 
where U and V are independently or together N, C, N(R13) where R13 is H, alkyl, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused arylycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S; or C(R16)(R17) where R16 and R17 are as defined above; and and n is 1 or 2.
The present invention further provides methods of synthesizing compounds of formula (A): 
wherein
Zxe2x80x2 is defined below;
R1 is alkyl or alkenyl optionally substituted with 1-3 halo or hydroxyl: -alkyl-C(O)OCH3; alkylamino, dialkylamino, alkyldialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C5-C12)aryl, (C5-C12)arylalkyl, (C5-C12)arylalkenyl, fused(C5-C12)aryl-cycloalkyl or fused(C5-C12)aryl-cyclalkylalkyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, xe2x80x94OC5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
X and Y are independently O, S or N, wherein N is optionally substituted with alkyl or alkenyl optionally substituted with 1-3 halo atoms; (C5-C6)aryl, arylalkyl or arylalkenyl optionally comprising 1-3 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; and
R2 and R3 are independently or together H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine; xe2x80x94RCORxe2x80x2, xe2x80x94RCOORxe2x80x2, xe2x80x94RNRxe2x80x2Rxe2x80x3Ro or xe2x80x94RC(O)NRxe2x80x2Rxe2x80x3 where R is alkyl or alkenyl, and Rxe2x80x2, Rxe2x80x3 and Ro are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C5-C12)aryl, (C5-C12)arylalkyl or (C5-C12)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, xe2x80x94OC5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
comprising the steps of:
(a) reacting a compound of formula (B): 
wherein M is Li or MgBr,
with an aldehyde of formula (C): 
where [PrG1] is a protecting group;
(b) removing the protecting group from the resulting alcohol (D)
(c) coupling the alcohol obtained from step (b) with an acid of formula (E):
Zxe2x80x2xe2x80x94COOHxe2x80x83xe2x80x83(E)
xe2x80x83and
(d) oxidizing the resulting product and further, if desired, removing the protecting group to yield the final compound.
According to one embodiment, the protecting group [PGR1] is removed from alcohol (D) by reacting the aldehyde of formula (C) with hydrochloric acid in dioxane. The protecting group [PGr1] may be any suitable group, preferably Boc.
According to another embodiment, the oxidation step of (d) is performed using Dess Martin reagent.
In a further embodiment, the compound of formula (B) is synthesized by:
(e) treating an acid of the formula (R1)COOH with thionyl chloride orboxalyl chloride;
(f) treating the resulting acid chloride with hydrazine to yield a hydrazide of the formula (R1)CONHNH2;
(g) reacting the hydrazide with triethyl orthoformate or trimethyl orthoformate and TsOH to yield a oxadiazole of the formula (F): 
xe2x80x83and
(h) treating the oxadiazole with butyllithium and further, is desired, reacting with MgBr.OEt2 to yield the compound B.
In one embodiment, Zxe2x80x2 is 
wherein
A is a direct bond, xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94NHxe2x80x94S(O)2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94Cxe2x80x94 or an amino acid selected from proline, isoleucine, cyclohexylalanine, cysteine optionally substituted at the sulfur with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; phenylalanine, homo-phenylalanine, dehydrophenylalanine, indoline-2-carboxylic acid; tetrahydrosioquinoline-2-carboxylic acid optionally substituted with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; tryptophan, tyrosine, serine or threonine optionally substituted with alkyl or aryl; histidine, methionine, valine, norvaline, norleucine, octahydroindole-2-carboxylic acid; asparagine, glutamine, omithine and lysine optionally substituted at the side chain nitrogen with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N, O and S; and
R4 is H, alkyl, alkenyl, or alkynyl; or cycloalkyl, alkylcycloalkyl, (C5-C12)aryl; (C5-C12)arylalkyl, fused (C5-C12)aryl-cycloalkyl or fused (C5-C12)aryl-cycloalkylalkyl optionally comprising one or more heteroatoms selected from N, O and S, and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, carboxyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamido, alkylthio or haloalkylthio or is absent; or Zxe2x80x2 may be 
xe2x80x83wherein
Rxe2x80x22 and Rxe2x80x23 are independently or together H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl or amidylguanidine; xe2x80x94RCORxe2x80x2, xe2x80x94RCOORxe2x80x2, xe2x80x94RNRxe2x80x2Rxe2x80x3Ro or xe2x80x94RC(O)NRxe2x80x2Rxe2x80x2 where R is alkyl or alkenyl, and Rxe2x80x2, Rxe2x80x3 and Ro are independently H, alkyl, alkenyl, cycloalkyl or (C5-C6)aryl; or cycloalkyl, alkylcycloalkyl; alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C5-C12)aryl, (C5-C12)arylalkyl or (C5-C12)arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, xe2x80x94OC5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio;
R13 is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S, and optionally substituted with halo or alkyl;
R14 is H, alkyl, alkenyl, amino, alkylamino, dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl, alkyl fused aryl-cycloalkyl, or aryloxycarboxamide optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, arylalkylcarboxamide, alkylthio or haloalkylthio; and
R15 is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino; or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused arylcycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from O, N and S.
In yet a further embodiment, Zxe2x80x2 is: 
where m is 0 or 1; n is 0 or 1;
D is a direct bond or an amino acid selected from proline, isoleucine, cyclohexylalanine, cysteine optionally substituted at the sulfur with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; phenylalanine, homo-phenylalanine, dehydrophenylalanine, indoline-2-carboxylic acid; tetrahydrosioquinoline-2-carboxylic acid optionally substituted with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; tryptophan, tyrosine, serine or threonine optionally substituted with alkyl or aryl; histidine methionine, valine, norvaline, norleucine, octahydroindole-2-carboxylic acid; asparagine, glutamine, omithine and lysine optionally substituted at the side chain nitrogen with alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl, or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising 1 or more heteroatoms selected from N, O and S; and
Axe2x80x2 is a direct bond, xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94NHxe2x80x94S(O)2xe2x80x94, xe2x80x94OC(O)xe2x80x94 orxe2x80x94Cxe2x80x94.
In yet another embodiment, Zxe2x80x2 is: 
xe2x80x83where
W is S or O;
R8 is alkylamino, dialkylamino or amino; and
R9 is H, alkyl or halo; or
Zxe2x80x2 is: 
xe2x80x83wherein
R10 is (C5-C6)aryl, (C5-C6)arylalkyl, (C5-C6)arylalkenyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl optionally comprising one or more heteroatoms selected from N, S and non-peroxide O, and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkylthio or haloalkylthio.
In a preferred embodiment, Zxe2x80x2 is: 
wherein
R11, R12 and E together form a monocyclic or bicyclic ring comprising 5-10 atoms selected from C, N, S and O; said ring containing 1 or more keto groups; and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkylthio, haloalkylthio or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C5-C12)aryl, (C5-C12)arylalkyl, ((C5-C12)arylalkyl)OC(O)NHxe2x80x94 or (C5-C12)arylalkenyl optionally comprising one or more heteroatoms selected from N, S and non-peroxide O, and optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, xe2x80x94C(O)O(alkyl), xe2x80x94C(O)(alkyl), alkylcarboxamide, alkylthio or haloalkylthio.
In a preferred embodiment, the invention provides a method of synthesizing a compound of formula (G): 
wherein
T is H or NH2;
R1 is alkyl or alkenyl optionally substituted with 1-3 halo or hydroxyl; a carboxylic acid ester such as -alkyl-C(O)OCH3; alkylamino, dialkylamino, alkyldialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C5-C12)aryl, (C5-C12)arylalkyl, (C5-C12)arylalkenyl, fused (C5-C12)aryl-cycloalkyl or fused (C5-C12)arylcyclalkylalkyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C5-C6)aryl, xe2x80x94Oxe2x80x94(C5-C6)aryl, arylcarboxamide, alkylthio or haloalkylthio; and
Ar is an aryl or arylalkyl optionally substituted with H, alkyl, amino, alkylamino, dialkylamino, halo or hydroxyl;
comprising the steps of:
(a) reacting a compound of formula (B): 
wherein M is Li or MgBr;
with an aldehyde of formula (C): 
where [PrG1] is a protecting group;
(b) removing the protecting group from the resulting alcohol (D)
(c) coupling the alcohol obtained from step (b) with an acid of formula (H): 
xe2x80x83wherein Txe2x80x2 is H or [PGr2]NH, where [PGr2] is a protecting group;
(d) oxidizing the resulting product to yield a ketone of formula (J): 
xe2x80x83and further, when Txe2x80x2 is [PGr2]NH,
(e) removing the protecting group [PGr2] to yield the compound of formula (G).
Preferably, [PGr2] is Cbz.
As used herein, the term xe2x80x9coptionally substitutedxe2x80x9d means, when substituted, mono to fully substituted.
As used herein, the term xe2x80x9cindependentlyxe2x80x9d means that the substituients may be the same or different.
As used herein, the term xe2x80x9calkylxe2x80x9d means C1-C15, however, preferably C1-C8.
As used herein, the term xe2x80x9calkenylxe2x80x9d means C1-C15, however, preferably C1-C8.
As used herein, the term xe2x80x9calkynylxe2x80x9d means C1-C15, however, preferably C1-C8.
It will be understood that alkyl, alkenyl and alkynyl groups, whether substituted or unsubstituted, may be linear or branched.
As used herein, the term xe2x80x9caryl,xe2x80x9d unless otherwise stated, means aryl groups preferably comprising 5 to 12 carbons, and more preferably 5 to 6 carbons. Unless otherwise indicated, the term includes both mono- and bi-cyclic fused ring systems. As used herein, where the term xe2x80x9carylalkylxe2x80x9d is defined by the general formula (Cx-Cy)arylalkyl, x and y refer to the number of carbons making up the aryl group. The alkyl group is as defined above. The term include mono-substituted alkyl groups (e.g., benzyl), as well as di-substituted alkyl groups such as -alkyl(aryl)2 (e.g., xe2x80x94CH(phenyl)2). The terms arylalkyl and alkyl fused arylcycloalkyl include (xcex1,xcex1)-disubstituted groups such as, for example, (xcex1,xcex1)-disubstituted benzyl and (xcex1,xcex1)-disubstituted 3,4-methylenedioxybenzyl groups, wherein the a substituents are preferably alkyl groups such as methyl, ethyl or propyl. Specific examples include (xcex1,xcex1)-dimethylbenzyl and (xcex1,xcex1)-dimethyl-3,4-methylenedioxybenzyl.
As used herein, the term xe2x80x9carylalkenylxe2x80x9d includes aryl groups where the alkenyl group comprises 1-3 or more double bonds. Exemplary arylalkenyl groups include xe2x80x94CHxe2x95x90CH2xe2x80x94aryl and xe2x80x94CHxe2x95x90CH-aryl, where aryl is preferably phenyl.
As used herein, the term xe2x80x9ccycloalkyl,xe2x80x9d unless otherwise stated, means cycloalkyl groups preferably comprising 3 to 12 carbons, and more preferably 3 to 6 carbons. Unless otherwise indicated, the term includes both mono-, bi- and tri-cyclic fused ring systems.
As used herein, the term xe2x80x9cCbzxe2x80x9d means benzyloxycarbonyl.
As used herein, the term xe2x80x9ccarboxamidexe2x80x9d is synonymous with amide; i.e., a group of the formula xe2x80x94NHC(O)xe2x80x94.
As used herein, the term xe2x80x9coxycarboxamidexe2x80x9d means a group of the formula xe2x80x94Oxe2x80x94C(O)NHxe2x80x94.
As used herein, the term xe2x80x9coxycarbonylxe2x80x9d means a group of the formula xe2x80x94OC(O)xe2x80x94.
Pharmaceutically acceptable salts of the compounds described above are within the scope of the invention.